Geraldine P. Schechter

Evidence for the Secretion of an Osteoclast Stimulating Factor in Myeloma

Abstract In an effort to describe the mechanism of bone erosion in patients with multiple myeloma, supernatant fluids from the short-term cultures of bone marrow aspirated from seven patients with myeloma were examined. Six contained a factor that stimulated osteoclastic bone resorption (calcium release greater than controls) in organ culture. This factor was biologically and chemically similar to osteoclast-activating factor, a mediator produced by phytohemagglutinin-activated normal peripheral blood leukocytes. Cultures of bone-marrow cells obtained from seven other patients with a variety of hematologic disorders did not produce a stimulator of bone resorption. Morphologic examination of autopsy and biopsy samples of bone from 37 patients with myeloma showed osteoclasts on bone-resorbing surfaces adjacent to areas of heavy myeloma-cell infiltration. It is suggested that osteolytic bone lesions and hypercalcemia in myeloma are due to the secretion of a soluble factor by myeloma cells that in turn stimul...

Primary Iron Overload in African Americans

PURPOSEnTo report African Americans with primary iron overload diagnosed during life and to study iron stores in African Americans undergoing autopsy.nnnPATIENTS AND METHODSnWe summarized information for 4 African-American patients diagnosed during life with iron overload not explainable by alcohol, blood transfusions, or ineffective erythropoiesis. We reviewed liver specimens and hospital records of 326 unselected adult African Americans who were autopsied, assessing Prussian blue-stained sections for hepatocellular iron and measuring iron quantitatively in specimens that stained positively. We calculated the hepatic iron index (the hepatic iron concentration in mumol/g dry weight divided by the age in years). In autopsy subjects we corrected the index to account for iron administered by blood transfusion (the adjusted hepatic iron index). The hepatic iron index is useful for distinguishing primary iron overload from the moderate siderosis that may accompany alcoholic liver disease. The normal index is < or = 1.0. An index > or = 1.7 cannot be explained by alcohol effects and an index > or = 1.9 indicates the magnitude of iron-loading found in Caucasian homozygous HLA-linked hemochromatosis.nnnRESULTSnThe 4 living patients, all males and 27 to 50 years of age, had elevated body iron burdens and one or more of the following: hepatomegaly, cirrhosis, cardiomyopathy, diabetes mellitus, and impotence. Hepatic iron indices were 2.3, 11.5, and 20.2 in the 3 whose liver iron concentrations were measured. Among the autopsy subjects, 4 (1.2%), 2 men and 2 women aged 50 to 63 years, had adjusted hepatic iron indices > or = 1.9 (range 1.9 to 5.6).nnnCONCLUSIONSnPrimary iron overload occurs in African Americans. Further studies are needed to define prevalence, pathophysiology and clinical consequences. Clinicians should look for this condition.

Lymphocyte Response to Blood Transfusion in Man

Abstract In 15 of 17 patients who received fresh or stored blood as whole blood or packed cells, a fivefold or greater rise in atypical lymphocytes or in vitro 3H-thymidine incorporation by blood leukocytes (or both) occurred one week after transfusion. These values declined to pretransfusion levels by the third week. The mean leukocyte 3H-thymidine incorporation at one week in these 17 patients (1067 disintegrations per second) was significantly greater than that found in five patients undergoing surgery without transfusion (423 disintegrations per second) or with an autotransfusion (457 disintegrations per second), or in three patients receiving frozen-thawed, leukocyte-depleted blood (163 disintegrations per second). Lymphocytotoxic reactivity was also detected in the serum of six of 12 patients. The frequency and timing of this cellular activation and its absence after administration of leukocyte-depleted blood favor an immunologic response to HL-A antigens on the transfused leukocytes and platelets a...

Marrow granulocyte reserves in black Americans: Hydrocortisone-induced granulocytosis in the “benign” neutropenia of the black

The bone marrow granulocyte reserves of nine black patients with benign neutropenia were estimated by measuring the maximum neutrophil increment after the administration of hydrocortisone. Thirty control subjects, including 16 black and 14 white adults, were also studied. The mean neutrophil increment in the black patients with neutropenia was significantly less than that in the control subjects. The mean increment in the black control was also significantly less than that in the white control subjects. Four of the 16 black control subjects had neutrophil counts below 2,000/microliter; if these four are excluded from the analysis, the difference between the black and white control subjects is no longer significant. These data suggest that there is a subpopulation of healthy black adults with neutrophil counts below 2,000/microliter with reduced marrow granulocyte reserves as tested by corticosteroids. Bone marrow aspirates in four of the neutropenic patients showed normal cellularity and myeloid maturation suggesting that the lower increments are due to a difference in granulocyte release rather than to a difference in granulocyte production.

Gene and microRNA analysis of neutrophils from patients with polycythemia vera and essential thrombocytosis: down-regulation of micro RNA-1 and -133a

BackgroundSince the V617F mutation in JAK2 may not be the initiating event in myeloprofilerative disorders (MPDs) we compared molecular changes in neutrophils from patients with polycythemia vera (PV) and essential thrombocythosis (ET), to neutrophils stimulated by G-CSF administration and to normal unstimulated neutrophilsMethodsA gene expression oligonucleotide microarray with more than 35,000 probes and a microRNA (miR) expression array with 827 probes were used to assess neutrophils from 6 MPD patients; 4 with PV and 2 with ET, 5 healthy subjects and 6 healthy subjects given G-CSF. In addition, neutrophil antigen expression was analyzed by flow cytometry and 64 serum protein levels were analyzed by ELISA.ResultsGene expression profiles of neutrophils from the MPD patients were similar but distinct from those of healthy subjects, either unstimulated or G-CSF-mobilized. The differentially expressed genes in MPD neutrophils were more likely to be in pathways involved with inflammation while those of G-CSF-mobilized neutrophils were more likely to belong to metabolic pathways. In MPD neutrophils the expression of CCR1 was increased and that of several NF-κB pathway genes were decreased. MicroRNA miR-133a and miR-1 in MPD neutrophils were down-regulated the most. Levels of 11 serum proteins were increased in MPD patients including MMP-10, MMP-13, VCAM, P-selectin, PDGF-BB and a CCR1 ligand, MIP-1α.ConclusionThese studies showed differential expression of genes particularly involved in inflammatory pathways including the NF-κB pathway and down-regulation of miR-133a and miR-1. These two microRNAs have been previous associated with certain cancers as well as the regulation of hyperthrophy of cardiac and skeletal muscle cells. These changes may contribute to the clinical manifestations of the MPDs.

Refocusing on history-taking skills during internal medicine training.

Recognizing that skilled history-taking is in danger of becoming a lost art, the American Board of Internal Medicine calls attention to the urgent need for internal medicine residency programs to ensure that these skills are taught and assessed. Although the Boards certification examination contains standardized items that test the physicians ability to use information from a patients medical history, the written examination cannot assess the physicians ability to elicit that history. The Board believes that history-taking skills will become even more crucial as health care delivery changes, requiring more cost efficiency without sacrificing quality. By highlighting the skills of effective history-taking and strategies for assessment, the Board offers specific recommendations for its promotion as a key element of quality patient care.

Cytomembranous inclusions in myelodysplastic syndrome.

A 56-year-old African-American man presented with fever of unknown origin and peripheral blood and bone marrow findings of myelodysplastic syndrome (MDS): refractory anemia with an excess of blasts in transformation that subsequently progressed to acute myeloblastic leukemia (AML). Ultrastructural study of two bone marrow specimens having the findings of MDS revealed frequent, large tubuloreticular structures (TRS) in lymphocytes, plasma cells, macrophages, and endothelial cells. Several cylindrical confronting cisternae (CCC) were present in macrophages and an endothelial cell. Two partially developed CCC were present in a plasma cell. TRS and CCC were not observed in eight subsequent bone marrow specimens obtained during the 9-month course of the AML. This is the first reported occurrence of TRS and CCC in MDS. These inclusions are probably related to an unidentified viral infection or possibly to cytokines released by the dysplastic hematopoietic cells.

Sea-blue histiocytes in a patient with lymphoma

A middle-aged man with lymphocytic lymphoma had numerous sea-blue histiocytes in his bone marrow, splenomegaly and thrombocytopenia. Thus, his illness mimicked that of patients with the primary syndrome of the sea-blue histiocyte. However, the paucity of sea-blue histiocytes in his spleen, the absence of neurologic disease, his age and the ultrastructure of his abnormal histiocytes were all evidence for the presence of the acquired syndrome. The pathogenesis of sea-blue histiocytosis and the relationship between acquired cases and the primary syndrome are discussed.

Fifth disease after immunoglobulin administration in an aids patient with parvovirus-induced red cell aplasia

H uman parvovirus B19 infection causes a number of clinical illnesses. Fifth disease (erythema infectiosum) and B19 arthropathy are felt to be immune-mediated phenomena, ’ whereas transient aplastic crisis and nonimmune fetal hydrops are due to viral destruction of erythroid precursors.’ In patients with impaired antibody response, such as those with the acquired immunodeficiency syndrome (AIDS), parvovirus infection can lead to persistent anemia through chronic destruction of erythroid precursors.” We present a case of a patient with AIDS and chronic parvovirus infection in whom extrinsic immunoglobulin administration appears to have precipitated an illness consistent with fifth disease and severe B19 arthropathy.

Finally, how myeloma lyses bone

For more than 25 years osteoclastic activation by myeloma tumor cells has been accepted as the explanation for the characteristic osteolytic lesions found in myeloma patients. But despite many suggested candidates, the activating factors involved have resisted definitive identification. In this